Ocular Safety: A Silent (In Vitro) Success Story

2002 ◽  
Vol 30 (2_suppl) ◽  
pp. 69-74 ◽  
Author(s):  
Rodger D. Curren ◽  
John W. Harbell
Keyword(s):  
Raw Materials ◽  
Test Methods ◽  
In Vitro Tests ◽  
High Dose ◽  
Animal Testing ◽  
Animal Test ◽  
Ocular Irritation ◽  
Irritation Test ◽  
Dose Levels

Ocular irritation testing has been one of the animal test methods most criticised by animal welfare advocates. Additional criticism has arisen from within the scientific community, based on the variability of the animal test results and the questionable relevance of the extremely high dose levels employed. As a result, the Draize eye irritation test has been one of the main targets for in vitro replacement. Despite extensive efforts, however, there is still no in vitro method that is fully validated as a regulatory replacement. In spite of this, many individual companies are using diverse in vitro ocular irritation tests to gain important safety and efficacy information about their products and raw materials, eliminating the need for animal testing in the process. This is done in a safe fashion by applying intelligent testing paradigms. ECVAM has played a major role in this success, through its many programmes that have emphasised the importance of understanding the true toxicological need, and then using in vitro tests to provide that information. Thus, even in the absence of a successfully validated regulatory assay, the desired result of reducing animal testing is being met.

Recent Progress in the Eye Irritation Test

1993 ◽  
Vol 9 (6) ◽  
pp. 1017-1025 ◽  
Author(s):  
Ih Chu ◽  
Peter Toft
Keyword(s):  
Animal Studies ◽  
In Vitro Tests ◽  
Animal Testing ◽  
Regulatory Requirements ◽  
Eye Irritation ◽  
Significant Development ◽  
In Vivo Test ◽  
Irritation Test

The rabbit eye irritation test based on the Draize method is required for the hazard assessment of chemicals and products that may come into contact with the eye. Due to the potential for the suffering of animals and subjectivity of the test, many modifications of the method have been made that involved a reduction in the number of animals and a refinement of techniques. Additionally, there has been significant development of in vitro alternatives. This paper reviews recent advances in the in vivo test and in vitro alternatives, as well as regulatory requirements. While the refinement of in vivo protocols has resulted in a reduction in the number and discomfort on animals, the development of in vitro alternatives could lead to an eventual replacement of animal studies. In view of the inherent simplicity of many in vitro methods, some of which comprise cell cultures, further research into the relevance/mechanism of effects is required. Batteries of in vitro tests, when properly validated, may be considered as replacements for animal testing.

scholarly journals Scientific discrepancies in European regulatory proposals on endocrine disruptors—REACH regulation quo vadis?

2021 ◽  
Author(s):  
Andreas Natsch
Keyword(s):  
Low Dose ◽  
Endocrine Disrupting Chemicals ◽  
Test Methods ◽  
Consumer Products ◽  
In Vitro Tests ◽  
In Vitro Test ◽  
Animal Testing ◽  
European Regulatory ◽  
Quo Vadis

AbstractThe EU chemical strategy for sustainability places a high focus on endocrine-disrupting chemicals (ED), the importance of their identification with increased testing and a ban in consumer products by a generic approach. It is assumed that for ED no threshold and hence no safe dose exists, leading to this generic approach. This view appears to be linked to the claim that for ED ‘low-dose non-monotonic dose response’ (low-dose NMDR) effects are observed. Without this hypothesis, there are no scientific reasons why classical risk assessment cannot be applied to the ED mode-of-action. Thus, whether for ED low-dose NMDR effects are considered a reproducible scientific fact by European authorities is Gretchen’s question in this politicized field. Recent documents by the SCCS, EFSA and ECHA reviewed herein illustrate the diverging views within European scientific bodies on this issue. Furthermore, ED researchers never replicated findings on low-dose NMDR in blinded inter-laboratory experiments and the CLARITY-BPA core studies could not find evidence for reproducible NMDR for BPA. ECHA proposes a battery of in vitro tests to test all chemicals for ED properties. However, these tests were never validated for relevance and their high positivity rate could lead to increased follow-up animal testing. Based on (i) lack of reproducibility data for low-dose NMDR, (ii) diverging views within European authorities on NMDR and (iii) lack of fully validated in vitro test methods it might be premature to fast-track the wide-ranging changes in the regulatory landscape proposed by the authorities ultimately leading to drastically increased animal testing.

Integrated Decision-tree Testing Strategies for Acute Systemic Toxicity and Toxicokinetics with Respect to the Requirements of the EU REACH Legislation

2008 ◽  
Vol 36 (1_suppl) ◽  
pp. 91-109 ◽  
Author(s):  
Robert Combes ◽  
Christina Grindon ◽  
Mark T.D. Cronin ◽  
David W. Roberts ◽  
John F. Garrod
Keyword(s):  
Decision Tree ◽  
Systemic Toxicity ◽  
Toxicity Tests ◽  
In Vitro Tests ◽  
The European Union ◽  
Animal Testing ◽  
Pbpk Modelling ◽  
Joint Research Project ◽  
The Eu

Liverpool John Moores University and FRAME conducted a joint research project, sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for acute systemic toxicity and toxicokinetic testing. The paper reviews in vitro tests based on basal cytotoxicity and target organ toxicity, along with QSAR models and expert systems available for this endpoint. The use of PBPK modelling for the prediction of ADME properties is also discussed. These tests are then incorporated into a decision-tree style, integrated testing strategy, which also includes the use of refined in vivo acute toxicity tests, as a last resort. The implementation of the strategy is intended to minimise the use of animals in the testing of acute systemic toxicity and toxicokinetics, whilst satisfying the scientific and logistical demands of the EU REACH legislation.

Parameters and Methods for Testing Artificial Heart Valves

1989 ◽  
Vol 12 (4) ◽  
pp. 252-260 ◽  
Author(s):  
J.C. Köhler ◽  
J.G. Tech
Keyword(s):  
Heart Valves ◽  
Close Correlation ◽  
Test Methods ◽  
In Vitro Tests ◽  
Geometrical Parameters ◽  
Test Standards ◽  
Artificial Heart Valves ◽  
Minimum Requirements ◽  
Definition Of

The report describes the development of heart valve test standards. The aim is comprehensive quality assurance by in vitro tests. The project includes three test fields: general basis, development and definition of test methods and test devices and comparative in vitro assessment of valves for the definition of minimum requirements. A preliminary list of test parameters and test steps has been defined: geometrical, flow, deformation, force, and conditioning parameters. A system of geometrical parameters has been developed for standardized aortic models. Geometrical parameters of 31 valves of six types and different sizes underline a close correlation between geometrical and hemodynamic parameters. The relative ostium cross-section Ae/AT increases with valve size and lies between 0.3 and 0.5. Two new measurement devices with quasi-steady flow are proposed as quick testers for leakage flow and pressure loss.

Dialogue and Collaboration: A Personal View on Laboratory Animal Welfare Developments in General, and on ECVAM's First Decade in Particular

2002 ◽  
Vol 30 (2_suppl) ◽  
pp. 207-210 ◽  
Author(s):  
Herman B.W.M. Koëter
Keyword(s):  
National Level ◽  
In Vitro Tests ◽  
Practical Application ◽  
Animal Testing ◽  
Validation Process ◽  
Personal View ◽  
Ld50 Test ◽  
The Three Rs ◽  
Regulatory Acceptance

A personal view is presented on progress made during the last 25 years in applying the Three Rs ( reduction, refinement, replacement) to animal testing in regulatory toxicology, with an emphasis on “good moments” (for example, international workshops on the principles and practical application of the validation process and on regulatory acceptance) and “not-so-good moments” (for example, the time taken to accept alternatives to the LD50 test and to accept in vitro tests for skin absorption as OECD Test Guidelines). The importance of dialogue and cooperation between international coordinating centres and scientific activities at the national level is stressed, as exemplified by the work of ECVAM during its first decade.

HYDRAULICS AND IN VITRO HEMOLYSIS TEST OF A MAGLEV IMPLANTABLE VENTRICULAR ASSIST DEVICE

2017 ◽  
Vol 17 (07) ◽  
pp. 1740023
Author(s):  
GUANGHUI WU ◽  
CHUANGYE XU ◽  
XIUJIAN LIU ◽  
CHANGYAN LIN ◽  
LIN YANG ◽  
...  
Keyword(s):  
Left Ventricular Assist Device ◽  
Ventricular Assist Device ◽  
Left Ventricular ◽  
Hydrodynamic Performance ◽  
In Vitro Tests ◽  
Animal Testing ◽  
Assist Device ◽  
Ventricular Assist ◽  
Left Ventricular Assist

A small implantable centrifugal left ventricular assist device, the CH-VAD (CH Biomedical Inc, JiangSu, China), featuring a magnetically levitated impeller is under development. The goal of this study is to validate hydrodynamic performance and hemocompatibility of the pump through in vitro studies. The hydraulic performance was quantified experimentally by using in vitro circulation loop system, and it turned out that the pump could deliver 5[Formula: see text]L/min under a pressure of 100[Formula: see text]mmHg at a rotational speed of approximate 3400[Formula: see text]rpm. A series of in vitro tests were established according to ASTM F1841, the standard practice for the assessment of hemolysis in continuous-flow blood pumps. The results showed that the average normalized index of hemolysis (NIH) value of the VAD was 0.0007[Formula: see text][Formula: see text][Formula: see text]0.0003[Formula: see text]mg/dL. The magnetic levitation left ventricular assist device (LVAD) has good hemolytic performance and stable mechanical property. These acceptable performance results supported proceeding initial acute animal testing conditions.

In Vitro Toxicology and the Test Guidelines

1996 ◽  
Vol 24 (3) ◽  
pp. 435-438
Author(s):  
Kimmo Louekari
Keyword(s):  
Cost Effective ◽  
Test Methods ◽  
In Vitro Tests ◽  
In Vitro Test ◽  
In Vitro Methods ◽  
Effective Manner ◽  
Genotoxic Carcinogens ◽  
Vitro Test

Ethical, economical and scientific considerations should encourage the development of alternative and in vitro test methods. Before their adoption, in vitro methods need to be validated and scientifically justified. Demand for rigorous validation schemes for in vitro tests must be emphasised, even more than in the case of in vivo tests. The OECD has adopted in vitro guidelines for testing genotoxicity; several endpoints and mechanisms can be studied in a cost-effective manner in vitro. Similar advantages could be afforded if acute irritation and corrosion, as well as the non-genotoxic carcinogenic effects of chemicals, could be studied in vitro. Evaluation of the validation status of various methods used to study non-genotoxic carcinogens was begun by the Nordic Working Group on In Vitro Methods for Non-genotoxic Mechanisms in 1996. In some established OECD test guidelines (for example, the dermal irritation/corrosion test), there is already room for the application of in vitro methods which have not been formally validated. In January 1996, the OECD Workshop on Harmonisation of Validation and Acceptance Criteria for Alternative Toxicological Test Methods set the basis for internationally acceptable principles to be followed in the validation of in vitro test methods.

scholarly journals Multidrug-resistant myeloma: laboratory and clinical effects of verapamil as a chemosensitizer

Blood ◽  
1991 ◽  
Vol 78 (1) ◽  
pp. 44-50 ◽  
Author(s):  
SE Salmon ◽  
WS Dalton ◽  
TM Grogan ◽  
P Plezia ◽  
M Lehnert ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Multidrug Resistance ◽  
Cytotoxic Agents ◽  
In Vitro Tests ◽  
High Dose ◽  
Clinical Effects ◽  
Myeloma Cells ◽  
Hodgkin's Lymphomas

Abstract Verapamil was evaluated as a chemosensitizer for reversing multidrug resistance in multiple myeloma both in vitro and in clinical trials. Bone marrows from 59 myeloma patients in relapse were evaluated for several resistance parameters: expression of p-glycoprotein (MDR1), doxorubicin (Adriamycin) and vincristine sensitivity, and the ability of added verapamil to reduce resistance to the cytotoxic agents. We found that verapamil was capable of sensitizing myeloma cells that exhibited resistance to doxorubicin and vincristine in vitro, but did not enhance sensitivity of cells that were drug sensitive (P less than .001). Myeloma cells expressing MDR1 immunohistochemically tended to be more doxorubicin resistant in vitro than MDR1-negative cells. In the clinical trials, 22 patients with myeloma refractory to vincristine- Adriamycin-dexamethasone (VAD) were treated with VAD plus high-dose intravenous verapamil (Ve). Among the 22 patients treated with VAD/Ve, five achieved a partial remission (23%). The median relapse-free survival for the VAD/Ve responders was 5.4 months and their overall survival from the start of VAD/Ve was better than that of the nonresponders. Among the subset of 10 patients whose myeloma cells were MDR1 positive, four responded clinically (40%), whereas none of five patients with MDR1-negative myeloma cells achieved remission with VAD/Ve. We also observed that myeloma cells from three of four VAD/Ve clinical responders exhibited in vitro chemosensitization with verapamil, whereas in vitro verapamil chemosensitization was seen in only one of six clinical nonresponders. Our observations demonstrate that clinical reversal of multidrug resistance can be achieved in some patients with VAD-refractory myeloma with the use of verapamil. In addition to their value in drug development, in vitro tests of MDR1 expression and of chemosensitizers plus cytotoxic drugs on the patients' bone marrow myeloma cells may identify patients who will respond clinically to chemosensitizer-containing regimens. We anticipate that chemosensitizer regimens capable of inhibiting multidrug resistance will play an increasing role in the treatment of hematologic malignancies, including B-cell neoplasms such as multiple myeloma and the non-Hodgkin's lymphomas.

In Vitro Assessment of Skin Irritation Potential of Surfactant-based Formulations by Using a 3-D Skin Reconstructed Tissue Model and Cytokine Response

2016 ◽  
Vol 44 (6) ◽  
pp. 523-532 ◽  
Author(s):  
Russel M. Walters ◽  
Lisa Gandolfi ◽  
M. Catherine Mack ◽  
Michael Fevola ◽  
Katharine Martin ◽  
...  
Keyword(s):  
Raw Materials ◽  
Skin Irritation ◽  
Clinical Testing ◽  
Personal Care ◽  
Animal Testing ◽  
Repeated Testing ◽  
Dermal Irritation ◽  
Testing Programme ◽  
Skin Irritation Test

The personal care industry is focused on developing safe, more efficacious, and increasingly milder products, that are routinely undergoing preclinical and clinical testing before becoming available for consumer use on skin. In vitro systems based on skin reconstructed equivalents are now established for the preclinical assessment of product irritation potential and as alternative testing methods to the classic Draize rabbit skin irritation test. We have used the 3-D EpiDerm™ model system to evaluate tissue viability and primary cytokine interleukin-1α release as a way to evaluate the potential dermal irritation of 224 non-ionic, amphoteric and/or anionic surfactant-containing formulations, or individual raw materials. As part of our testing programme, two representative benchmark materials with known clinical skin irritation potential were qualified through repeated testing, for use as references for the skin irritation evaluation of formulations containing new surfactant ingredients. We have established a correlation between the in vitro screening approach and clinical testing, and are continually expanding our database to enhance this correlation. This testing programme integrates the efforts of global manufacturers of personal care products that focus on the development of increasingly milder formulations to be applied to the skin, without the use of animal testing.

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